title: Repression of ATR pathway by miR-185 enhances radiation-induced apoptosis and proliferation inhibition.
abstract: Cellular responses to DNA damage induced by intrinsic and extrinsic genotoxic stresses are highly regulated by complex signaling pathways, such as activation of the phosphoinositide-3-kinase-like protein kinase family and their downstream genes. Disruption of these signaling pathways leads to genome instability and cell death, and thus may provide potential novel strategies for cancer therapy. Here, we find that the expression of a human microRNA (miRNA), hsa-miR-185, is downregulated in response to ionizing radiation. Elevation of miR-185 sensitizes renal cell carcinoma cells to X-rays both in vitro and in vivo. Bioinformatic analysis shows that the ATM- and Rad3-related (ATR) kinase, a master conductor of cellular responses to DNA damage and DNA replication stresses, is a target of miR-185. This prediction was validated by luciferase reporter and mutation assays. We also demonstrated that miR-185 negatively regulates ATR expression at post-transcriptional level. miR-185 enhances radiation-induced apoptosis and inhibition of proliferation by repressing ATR pathway. In conclusion, our findings indicate a previously unreported regulatory mechanism for ATR expression mediated by miR-185 and shed light on the potential application of miRNAs both as direct cancer therapeutics and as tools to sensitize tumor cells to radiotherapy.
authors.affiliation: Department of Space Radiobiology, Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: He
authors.forename: F
authors.initials: F
authors.lastname: Su
authors.forename: N
authors.initials: N
authors.lastname: Ding
authors.forename: W
authors.initials: W
authors.lastname: Hu
authors.forename: B
authors.initials: B
authors.lastname: Yao
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D011836:Radiation Tolerance; D059467:Transcriptome / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C552431:MIRN185 microRNA, human; D035683:MicroRNAs; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins